Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of a variety of conditions associated with pain, fever and inflammation, including osteoarthritis, rheumatoid arthritis, gout and ankylosing spondylitis. They are also widely used for treating acute pain associated with injuries and surgical procedures (including dental procedures) and headaches. The beneficial effects of NSAIDs are largely believed to be attributable to their ability to suppress prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
However, long-term use of NSAIDs is significantly limited by their ability to cause clinically significant injury in the gastrointestinal tract (Wallace, J. L. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology. 1997; 112:1000-1016). Selective inhibitors of COX-2 were seen as an advance on conventional NSAIDs, as they appeared to cause less gastrointestinal injury. However, concerns have been raised regarding the cardiovascular toxicity these drugs, and possibly also regarding conventional NSAIDs (Grosser et al., Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006; 116: 4-15).
It is well known that NSAIDs stimulate leukocyte adherence and reduce gastric mucosal blood flow, and these actions are widely held to be important contributors to the pathogenesis of NSAID-induced gastrointestinal damage (Wallace, 1997). Induction of leukocyte adherence by non-selective and COX-2-selective NSAIDs may also contribute to cardiovascular complications of these drugs.
Recently, it has been observed that hydrogen sulfide (H2S) exerts anti-inflammatory and analgesic activities. H2S is an endogenous substance, produced in many tissues and affecting many functions (Wang, Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 2002; 16: 1792-1798). It has also been shown to be a vasodilator and can suppress leukocyte adherence to the vascular endothelium (Wang, 2002; Fiorucci et al., Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology. 2005; 129: 1210-1224). Further, Fiorucci et al. (2005) have demonstrated that pretreatment with an H2S donor can diminish the severity of NSAID-induced gastric damage in the rat.
Surprisingly, the inventors have shown in the present application that the anti-inflammatory activity of a variety of NSAIDs is significantly enhanced when covalently linked to or NSAID salts are formed with an H2S releasing moiety. Further, these NSAID derivatives have been shown to have reduced side effects. In particular, the inventors have shown that NSAID derivatives of the present invention have one or more of the following additional characteristics: (1) produce less gastrointestinal injury than conventional NSAIDs; (2) accelerate the healing of pre-existing gastric ulcers; and (3) elicit significantly less of an increase in systemic blood pressure than conventional NSAIDs. Furthermore, the NSAID derivatives of the present invention reduce leukocyte adherence to the vascular endothelium, which may contribute to both reduced gastrointestinal and cardiovascular side effects.